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Kunert A, Chmielewski M, Wijers R, et al. Intra-tumoral production of IL18, but not IL12, by TCR-engineered T cells is non-toxic and counteracts immune evasion of solid tumors. Oncoimmunology. 2017;7(1):e1378842doi: 10.1080/2162402X.2017.1378842.
Kunert, A., Chmielewski, M., Wijers, R., Berrevoets, C., Abken, H., & Debets, R. (2017). Intra-tumoral production of IL18, but not IL12, by TCR-engineered T cells is non-toxic and counteracts immune evasion of solid tumors. Oncoimmunology, 7(1), e1378842. https://doi.org/10.1080/2162402X.2017.1378842
Kunert, A, et al. "Intra-tumoral production of IL18, but not IL12, by TCR-engineered T cells is non-toxic and counteracts immune evasion of solid tumors." Oncoimmunology vol. 7,1 (2017): e1378842. doi: https://doi.org/10.1080/2162402X.2017.1378842
Kunert A, Chmielewski M, Wijers R, Berrevoets C, Abken H, Debets R. Intra-tumoral production of IL18, but not IL12, by TCR-engineered T cells is non-toxic and counteracts immune evasion of solid tumors. Oncoimmunology. 2017 Oct 11;7(1):e1378842. doi: 10.1080/2162402X.2017.1378842. eCollection 2017. PMID: 29296541; PMCID: PMC5739571.
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Oncoimmunology. 2017 Oct 11;7(1):e1378842. doi: 10.1080/2162402X.2017.1378842. eCollection 2017.

Intra-tumoral production of IL18, but not IL12, by TCR-engineered T cells is non-toxic and counteracts immune evasion of solid tumors.

Oncoimmunology

A Kunert, M Chmielewski, R Wijers, C Berrevoets, H Abken, R Debets

Affiliations

  1. Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
  2. Department I of Internal Medicine, University Hospital Cologne and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.

PMID: 29296541 PMCID: PMC5739571 DOI: 10.1080/2162402X.2017.1378842

Abstract

Adoptive therapy with engineered T cells shows promising results in treating patients with malignant disease, but is challenged by incomplete responses and tumor recurrences. Here, we aimed to direct the tumor microenvironment in favor of a successful immune response by local secretion of interleukin (IL-) 12 and IL-18 by sadministered T cells. To this end, we engineered T cells with a melanoma-specific T cell receptor (TCR) and murine IL-12 and/or IL-18 under the control of a nuclear-factor of activated T-cell (NFAT)-sensitive promoter. These T cells produced IL-12 or IL-18, and consequently enhanced levels of IFNγ, following exposure to antigen-positive but not negative tumor cells. Adoptive transfer of T cells with a TCR and inducible (i)IL-12 to melanoma-bearing mice resulted in severe, edema-like toxicity that was accompanied by enhanced levels of IFNγ and TNFα in blood, and reduced numbers of peripheral TCR transgene-positive T cells. In contrast, transfer of T cells expressing a TCR and iIL-18 was without side effects, enhanced the presence of therapeutic CD8

Keywords: T cells; TCR gene therapy; cytokines; solid tumors; tumor microenvironment

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